The progressive aging of the world's population brings on the undesired consequence of increasing the occurrence of senile dementia. Alzheimer's Disease (“AD”) is a form of senile dementia. AD is a heterogeneous group of dementias that share common clinical symptoms, involving progressive cognitive impairments. This form of senile dementia is characterized by two kinds of pathological deposits in specific areas of the brain, called senile plaques and neurofibrillary tangles (“NFTs”).
Senile plaques contain extracellular deposits of beta-amyloid protein (“Aβ”) associated with degenerating nerve processes known as dystrophic neuritis. Initial deposits are non-fibrillar (a diffuse plaque), but are progressively transformed into fibrils, giving rise to the characteristic amyloid plaques. NFTs form inside neuronal cells that die during the course of the disease and consist primarily of adnormal paired helical filaments (“PHFs”). However, large numbers of senile plaques are found in some cognitively normal individuals, suggesting that not only their presence, but also the coexistence of NFTs is required for dementia. On the other hand, large numbers of NFTs in cerebral cortex and hippocampus closely correlate with the degree of dementia in AD. Thus, the accumulation of neurofibrillary lesions may represent a final pathway that leads to neuronal cell death and neuorodegeneration. Dorronsoro et al., 2002, vol. 12, 1527-1536.
Furthermore, at the moment, researchers are trying to design new drugs useful in treatment of senile plaques and NFTs that are formed by PHFs whose main component is tau. PHF consists of hyperphosphorylated tau and contains a small amount of ubiquitin. Tau is one of the microtubule-associated proteins and is specifically localized in the neuron. The tau protein is essentially for stability of neuronal cytoskeleton, but in PBF, it is abnormally phosphorylated. Dorronsoro et al., 2002, vol. 12, 1527-1536.
Glycogen synthase kinase 3 beta (“GSK-3β”) is involved in tau modifications leading to PHF. It is important to note that the inhibition of GSK-3β is accepted as a promising strategy for the treatment of AD and other neurodegenerative diseases.
GSK-3 is a key regulator of glycogen synthase, one of the principal modulators of glycogen metabolism and hence glucose levels. GSK-3 is a serine/threonine kinase for which two isoforms, GSK-3α and GSK-3β have been identified. These two isoforms share 97% sequence similarity within their kinase catalytic domains but differ significantly from one another outside this region, with GSK-3α possessing an extended N-terminal glycine-rich tail. The two isoforms are encoded by two different mRNAs that are variably expressed in different tissues. Accordingly, the GSK-3 β is highly expressed in the lungs, kidneys, and brain whereas the GSK-3α is highly expressed in the lungs, ovaries, kidneys, and testis. Furthermore, over expression of GSK-3β in the brain of adult mice was found to produce neurodegeneration exhibiting many of the characteristics of AD, including tau hyperphosphorylation. Indeed, an over-expressed GSK-3 has been linked to all the primary abnormalities associated with AD. The term over-expressed herein means to over manifest the effects of GSK-3. Imahori et al., vol. 121, 179-188.
The number of GSK-3 inhibitors as therapeutic candidates in development is still limited. Which, in turn, leads us to the present invention. The present invention presents 11C and 18F labeled inhibitors of GSK-3 wherein these labeled inhibitors can be investigated by a medical imaging technique such as Positron Emission Tomography (“PET”), MRI, CT, ultrasound, X-ray imaging, or optical imaging.
Before moving forward, it is important to further characterize the relationship between PET and 11C and 18F. A group of diagnostic Positron Emission Tomography (“PET”) procedures utilize radioactive labeled compounds, wherein the radioactive atoms are positron emitters. Some examples of positron emitting elements include nuclides of carbon, nitrogen, or fluorine. These elements are the backbone of almost all biological active compounds. In order to be able to use these elements, stable isotopes are replaced with a radioactive isotope. The radioactive labeled compounds, called tracers, are transported, accumulated and converted exactly the same way as for non-radioactive compounds. The PET method has possibilities to detect malfunction on a cellular level in the investigated tissues or organs. The method is very sensitive and requires only nanomole quantities of produced radioactive tracers. These radioactive tracers have a half-life in the range from 2 to 110 minutes, (e.g. 11C, t1/2=20.4 minutes, 18F, t1/2=110 minutes). Acta Upsaliensis, Uppsala 2002, ISBN 91-554-5452-6. Because of the radioactivity, the short half-lives and the submicromolar amounts of the labeled substances, extraordinary synthetic procedures are required for the production of these tracers.
Some peptides such as a heat resistant GSK-3 binding protein and a synthetic peptide inhibitor have recently been reported as GSK-3 inhibitors. Other reported GSK-3 inhibitors include purine and pyrimidine derivative compounds, azoles, maleimide derivatives, and ATP-non-competitive inhibitors are in development or have been discovered. However, radiolabeled inhibitors have not been reported. Accordingly, the present invention introduces novel 11C/18F-labeled analogue inhibitors of GSK-3 that can then be investigated by medical imaging techniques.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.